Transcript Predicting the Evolution of Influenza

Evolution of influenza A
Rachel Albert
Craig Bland
http://freeowl.net/blog/2009/09/30/whos-scared-of-the-big-bad-h1n1
Influenza A
• Responsible for 20,000 American deaths annually.
• Genome consists of 8 RNA strands that code for 11
proteins including coat proteins.
• Divided into 16 Hemagglutinin (H1-H16) and 9
neuraminidase (N1-N9) subtypes (H1N1).
• H1 & H3 infect humans
• Hemagglutinin has five antigenic sites that allow for the
host’s immune system to recognize, attack, and
remember.
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Why has Influenza been such an effective virus?
• Lack enzymes that check for replication
errors.
• Antigenic drift has strong influence.
• Positive selection- more nonsilent
mutations than silent.
• Host immune system forces virus to
evolve.
Arthur Chun-Chieh Shih et al
• Wanted to determine the
rate at which the flu
evolves and how it
evolves.
• Frequency Switchreplacement of one major
amino acid by another
between successive years.
• Effective Switch- when
new amino acid becomes
fixed in a population for 1
year.
• Total Switches:130
• Effective Switches:95
• 57 out of the 95 occurred
at known antigenic
epitopes.
• Including 8 that are also
receptor binding sites.
Effective switches.
130 switches and the sites at which they occurred.
Shih A C et al. PNAS 2007;104:6283-6288
©2007 by National Academy of Sciences
Transition Time
Walter Fitch and Colleagues
• Hypothesized that flu strains with
novel antigenic sites would have a
selective advantage.
• Examined frozen hemagglutinin
genes over a 20 year span.
• Two patterns emerged :

Nucleotide Substitutions at 6.7
X 10-3 per nucleotide per year

Most of the frozen flu strains
were extinct by the 1980’s
Why did some lineages survive while others perished?
• Nucleotide
substitutions resulting
in amino acid
replacements in
hemagglutinin’s
antigenic sites rather
then nonantigenic sites
In antigenic
sites
In nonantigenic
sites
Surviving
Lineages
33
10
Extinct Lineages
31
35
Robin M. Bush and colleagues (1999)
• Wanted to understand
influenza evolution.
• Hypothesized the neutral
theory of molecular
evolution

1) mutations that alter
amino acid replacements
are deleterious

2) silent mutations may
become fixed in
population.
• Looked at 331 nucleotide
substitiutions
• 58% were silent
• 42% replacement.
• Results consistent with
neutral theory.
• However, some areas did not fit neutral
theory.
• Found that 18 codons had nonrandom
mutations (hypervariable regions)
• These codons had 9 silent, and 123 nonsilent
substitutions.
• All of the 18 codons determined which amino
acid would be present in a HA antigenic site.
• Determined that host immune system forces
strong selection on HA genes.
Predicting the Evolution of Influenza
(Bush et al. 1999)
• Wanted to develop a method to predict future viral strains of Influenza.
• Identified a small set of 18 rapidly evolving codons (5.7 X 10-3) which improves
viruses fitness.
• They found a significant overlap between the positively selected codons and the
codons in or near antibody binding sites.
• Their methods can be used to monitor the viruses currently in the population to
help identify positively selected codons which may have a predictive value for
determining future progeny.
Why important?
• Understanding flu
evolution allows us to
better predict vaccines.
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Future Research
• More Research performed to better predict
Influenza A virus
• Investigate the use of chicken eggs and its effect
on deadly Avain flu virus showing up in human
populations.
Works Cited
• Bush, Robin M.,Catherine A. Bender, Kanta Subbarao, Nancy J. Cox, Walter
M. Fitch. “Predicting the Evolution of Human Influenza A.”Science 286
(1999):1921-1925.
• Bush, Robin M., and Walter M. Fitch. "Positive Selection on the H3
Hemagglutinin Gene of Human Influenza." Molecular Biology and Evolution
16.11 (1999): 1457-465.
• Freeman, Scott, and Jon C. Herron. Evolutionary Analysis. Upper Saddle River,
NJ: Pearson Prentice Hall, 2007. 531-37.
• Shih, A. C.-C., T.-C. Hsiao, M.-S. Ho, and W.-H. Li. "Simultaneous Amino
Acid Substitutions at Antigenic Sites Drive Influenza A Hemagglutinin
Evolution." Proceedings of the National Academy of Sciences 104.15 (2007):
6283-288.